New Cytotoxic Agents for the Treatment of Breast Cancer

New Cytotoxic Agents for the Treatment of Breast Cancer

ABSTRACT:
Over the past 5 years, many new cytotoxic
agents with activity against metastatic cancer have been discovered,
and several are currently undergoing clinical trials. Whether
their marked degree of activity represents a real difference compared
with that of drugs developed in the past 2 decades or simply reflects
changes in methodology is difficult to ascertain, as is the most
appropriate setting in which to employ these agents in the management
of breast cancer. It is unlikely that any of these agents alone
will change the natural history of metastatic breast cancer. In
the future, such options as adding these single agents to existing
combinations, substituting these agents for other agents in existing
combinations, or developing entirely new combinations with emerging
new agents need to be explored. These new combinations must then
be compared with existing and commonly used combinations to determine
which option should be used as the treatment of choice for untreated
patients with metastatic breast cancer. [ONCLOGY 10(Suppl):21-29,
1996]

Introduction

Over the past 10 years, several new treatment strategies have
been developed and many new agents have been evaluated for the
treatment of metastatic breast cancer [1]. Some of these agents
represent analogs of previously existing drugs, whereas others
belong to new molecular families. Some agents have novel mechanisms
of action, different from those of drugs used in the past. Several
agents have been approved by the regulatory agencies for the treatment
of breast cancer; others are still completing clinical evaluation,
and many more are in preclinical evaluation. In this article,
I will review agents with demonstrated efficacy against breast
cancer (Table 1).

Amonafide

Amonafide (benzisoquinolinedione, nafidimide) is a synthetic compound
with potent antiviral and cytotoxic activity. It acts as a DNA-intercalating
agent and is an inhibitor of topoisomerase II [2]. Phase I trials
using 3 different schedules were conducted: daily ´ 5 every
3 weeks, bolus infusion every 3 to 4 weeks, and 24-hour continuous
infusion every 4 weeks. The dose-limiting toxicity was reversible
myelosuppression. Nonhematologic toxicity was mild, consisting
mostly of nausea and vomiting, which was easily controlled with
antiemetics. The daily ´ 5 schedule of administration was
recommended for phase II trials. The recommended phase II dosage
was 300 mg/m² daily for 5 consecutive days. The daily dose
was administered over 1 hour. Amonafide has modest antitumor activity
against prostate and small-cell lung cancer. Three phase II trials
performed in patients with breast cancer have been reported [3-5].
The overall activity of the drug was modest, between 15% and 20%.
Two complete remissions were observed among 103 patients. The
response rate was modest, even in patients who had undergone no
prior chemotherapy.

Amonafide is acetylated to N-acetyl- amonafide [6,7]. Because
of the known, marked individual variation in plasma concentration
of N-acetyl-amonafide, an acetylator phenotype was determined
in a small group of patients. Fast acetylators were found to have
a much higher overall response rate (3 of 8; 38%) than slow acetylators
(1 of 16; 6%).5 An acetylator phenotype also correlated with toxicity,
suggesting that the recommended phase II dose was too high for
fast acetylators and too low for slow acetylators (Table 2). Additional
trials are indicated for this agent to confirm this latter observation,
which suggests that in a subgroup of patients with breast cancer,
amonafide has marked antitumor activity. Dosing based on an acetylator
phenotype is being tested prospectively to improve the therapeutic
ratio of this agent. Because extramedullary toxicity is modest,
additional dose-escalation studies, perhaps with hematopoietic
growth factor support, would be indicated to assess the full range
of doses with this agent.

New Anthracyclines

Anthracyclines are the most active single agents in the treatment
of breast cancer, but their clinical usefulness is limited by
cardiotoxicity related tocumulativedos[8].Epirubicin is a potentially
less cardiotoxic doxorubicin analog, but it has not been approved
by the Food and Drug Administration (FDA) because of insufficient
supportive evidence. Several new anthracycline derivatives have
entered clinical trials, and a few of them have been evaluated
against metastatic breast cancer [8].

Theprubicin underwent phase II evaluation in the 1980s;
several trials suggested activity equivalent to that of doxorubicin
[9,10]. Limited phase II trials of theprubicin in combination
therapy suggested no difference in activity between theprubicin-
and doxorubicin-containing combinations [11]. However, no direct
comparative trials have been reported.

Liposomal Doxorubicin (TLC D-99)--A new approach to reduce
the toxicity of anticancer drugs is to encapsulate otherwise soluble
drugs into multilamellar lipid particles (liposomes). Doxorubicin
is the single most studied anticancer drug encapsulated in liposomes.
TLC D-99 was developed with the intent of reducing the cardiotoxicity
of doxorubicin. Phase I trials determined that an intermittent
3-weekly schedule was appropriate, and the maximum tolerated dose
was found to be between 60 and 90 mg/m². Activity was similar
to that of other anthracyclines in limited phase II studies [12].
In combination with standard agents, liposomal doxorubicin achieved
efficacy similar to that of standard anthracycline-containing
regimens [13]. To date, results suggest that higher cumulative
doses can be administered with a lower incidence of and less severe
cardiotoxicity than those of the soluble free agent. However,
comparative trials to determine the relative efficacy and safety
of this agent are just completing accrual. Other liposome-encapsulated
anthracyclines are entering phase I/II studies, but the results
of such studies have not yet been published.

Anthrapyrazoles

The anthracenediones (mitoxantrone [Novantrone], bisantrene, and
others) were developed to reduce the frequency and severity of
anthracycline-induced cardiotoxicity [14]. Although mitoxantrone
is less cardiotoxic than the anthracyclines, it is also somewhat
less effective. For this reason, mitoxantrone has not received
FDA approval for treatment of breast cancer. The anthrapyrazoles
are structurally similar to mitoxantrone [15]. They maintain the
planar conformation and cationic nature of the anthracyclines,
essential for DNA intercalation. Several anthrapyrazoles have
been developed.

Losoxantrone (CI-941)--Preclinical evaluation demonstrated
that losoxantrone induced both single- and double-stranded breaks
in DNA and was a potent inhibitor of DNA synthesis [16]. In preclinical
models, it was less cardiotoxic than doxorubicin [17]. Phase I
clinical trials demonstrated that when losoxantrone was administered
in an intermittent single-dose schedule, the maximum tolerated
dose was 55 mg/m², and the dose-limiting toxicities were
leukopenia and neutropenia [18].

At least two phase II studies of losoxantrone have been reported
[19,20]; both included previously untreated and previously treated
patients with metastatic breast cancer. The objective response
rates obtained in these studies are shown in Table 3. A few complete
remissions were observed, and response durations in these trials
compared favorably with those expected after standard combination
chemotherapy. Toxicity consisted mostly of leukopenia, although
up to 40% of patients were reported to have alopecia. Acute toxicity
was negligible. However, a recent update reported that 3% of patients
developed congestive heart failure [21]. Therefore, this agent
is as active as or more active than existing anthracyclines; however,
the drug is not devoid of cardiotoxicity.

Teloxantrone (CI-937)--This second anthrapyrazole has also
completed phase I/II clinical trials [22,23]. At least one phase
II study in breast cancer has been reported in abstract form [23].
At an early stage of follow-up, there were major objective responses
in 9 of 47 patients, and a minor response was achieved in another
11% (Table 3). No additional information is available about this
trial. The pattern, frequency, and severity of toxicity appeared
to be similar to those of losoxantrone.

Piroxantrone--Piroxantrone hydrochloride (oxantrazole,
NSC-349174) is the third anthrapyrazole compound currently undergoing
testing in clinical trials [24]. No reports of its activity in
breast cancer are available at this time.

Camptothecin Analogs

Topoisomerases are recognized targets for anticancer agents. Topoisomerase
I makes a single cut in the DNA duplex and relieves transcription-associated
torsional strain. Camptothecin, a plant alkaloid with broad-spectrum
activity and a novel mechanism of action, was isolated from Camptotheca
acuminata more than 2 decades ago. In the early 1970s, phase
I clinical trials showed marked hematologic and nonhematologic
toxicity, including severe cystitis; this led to the conclusion
that the compound was too toxic for clinical development. More
recently, several novel semisynthetic and synthetic analogs designed
to be less toxic and to overcome the problems associated with
pharmaceutical formulations of natural products have appeared.
These analogs are completing clinical development. The parent
compound and the recently developed analogs inhibit both DNA and
RNA synthesis by topoisomerase I-mediated effects [25]. The analogs
of interest in the area of breast cancer research and treatment
include topotecan, irinotecan, and probably SN-38. The relative
efficacy and toxicity of the camptothecin analogs were evaluated
in preclinical models [26].

In phase II trials, topotecan was administered at a dosage of
1.5 mg/m² daily for 5 consecutive days to patients with metastatic
breast cancer who had received minimal or no prior chemotherapy
treatment. Cycles of treatment were repeated every 3 weeks [27].
Sixteen patients had been treated at the time of the report, 14
of whom were evaluable. Five patients achieved a partial response
(36%), and 1 patient achieved a minor response. Three patients
had stable disease, with the remaining five patients showing progression
of metastatic disease. Myelosuppression, especially granulocytopenia,
was observed. Mild fatigue, mild to moderate alopecia, and skin
rashes were also reported.

Irinotecan (CPT-11) is another water-soluble camptothecin
analog. Although it also is a topoisomerase I inhibitor, unlike
camptothecin and topotecan, CPT-11 has limited antitumor activity
in vitro. In vivo, it is converted to 7-ethyl-10-hydroxy-camptothecin
(SN-38), a metabolite with a 100-fold greater antitumor activity
than CPT-11 in vitro. This agent has antitumor activity against
small-cell and non-small-cell lung cancer, gynecologic and gastrointestinal
tumors, and leukemia and lymphoma. Until recently, severe side
effects, such as leukopenia and diarrhea, had limited its clinical
development.

In a recently reported phase II trial, irinotecan was administered
to patients with metastatic breast cancer who had undergone minimal
or no prior chemotherapy [28]. The agent was administered intravenously
over 30 minutes at a dosage of 350 mg/m² every 3 weeks. Of
29 patients treated, 21 were evaluable at the time of the report;
these patients had a good performance status and a moderate amount
of tumor burden. Twelve patients were evaluable for response.
One achieved a complete remission, whereas four others ex- perienced
no change. The remaining seven patients had progressive disease.
Grade II or higher nausea and vomiting, diarrhea, abdominal cramps,
alopecia, neutropenia, asthenia, and hot flashes were reported.
Three patients were removed from the study because of toxicity.

In a second study, reported in abstract form only, 15 (23%) of
65 patients responded to irinotecan treatment [29]. No information
is available about the duration of treatment or the effect of
camptothecin analogs on quality of life.